Cyclooxygenase-2 inhibitors decrease interleukin-1beta-stimulated prostaglandin E2 and IL-6 production by human gingival fibroblasts

Previous work showed that normal and aggressive periodontitis (AgP) gingival fibroblasts produce the bone-resorbing cytokine IL-6. PGE2 is important in regulating IL-6 production. Non-steroidal anti-inflammatory drugs inhibit PG synthesis via COX-1 and/or COX-2 isoenzymes and may inhibit periodontal destruction. COX-2 is induced after cellular activation (i.e., by inflammatory cytokines such as IL-1beta). Little is known about IL-1beta-stimulated AgP fibroblast IL-6 and PGE2 production and their regulation by COX inhibitors. The objective of this study was to determine the effects of COX-2 inhibitors on amounts of PGE2 and IL-6 made by IL-1beta-stimulated gingival fibroblasts. Gingival fibroblasts (2.5 x 10(4)) from healthy or severe periodontitis patients were cultured in serum-free medium, with or without IL-1beta (10(-11)M) for 24 hours, with or without the COX-1/2 inhibitor indomethacin or the selective COX-2 inhibitors NS-398, celecoxib, or rofecoxib. PGE2 and IL-6 in culture supernatants were determined by specific enzyme-linked immunosorbent assay (ELISA)s. All of the COX inhibitors caused dose-dependent decreases in IL-1beta-stimulated PGE2, to a maximum of > 90% in all cell lines (P < or = 0.0001). The selective COX-2 inhibitors, but not indomethacin, caused partial (generally up to approximately 60%), dose-dependent decreases in IL-1beta-stimulated IL-6 in all cell lines (P < or = 0.003). When exogenous PGE2 was added concurrently with COX-2 inhibitors before addition of IL-1beta, IL-6 production returned to levels at or approaching that produced by cells exposed only to IL-1beta (P < or = 0.04). The results suggest that COX-2 inhibition may be useful in helping to control fibroblast production of IL-6 in patients with severe periodontitis.